Steroid-refractory immune checkpoint inhibitor (ICI) hepatitis and ICI rechallenge: A systematic review and meta-analysis

Background: In recent years, the use of immune checkpoint inhibitors (ICIs) has become a cornerstone in cancer treatment. However, this has also resulted in the emergence of immune-related adverse events, notably ICI hepatitis, posing a significant clinical challenge. While steroids are the primary treatment, there are increasing cases of steroid-refractory ICI hepatitis. Our objective is to investigate the management of ICI hepatitis and its response to steroid treatment. Methods: PubMed/MEDLINE, EMBASE, and CENTRAL databases were searched in July 2023 based on keywords including ICIs (anti–Programmed cell death protein 1/Programmed Death-Ligand 1, anti–CTLA–4, and anti-LAG3) and hepatitis. Results: A total of 4358 studies were screened, and 44 studies were included in this systematic review. One thousand eight hundred fifty-six patients with ICI hepatitis were included (grade 1-2: 31.7%, grade 3-4: 56.0%, and unknown: 12.3%) with 1184 patients who received corticosteroid treatment. The duration of treatment and dosage varied considerably across the studies. Mycophenolate mofetil was the predominant agent used in 68 out of 82 cases (82.9%), followed by infliximab and azathioprine. A summary estimate of the proportion of steroid-refractory hepatitis in a random effects model was 16% (95% CI: 11%–23%). An estimated 40% (95% CI: 30%–51%) of patients of all patients with ICI hepatitis were rechallenged with an ICI, and of those rechallenged, there was an estimated 22% (95% CI: 15%–30%) recurrence. Conclusions: Corticosteroids are the primary treatment for ICI hepatitis, with mycophenolate mofetil used as a secondary option for steroids-refractory cases. Current practices mostly rely on expert consensus, highlighting the need for further research to validate and optimize these treatments, particularly for steroid-resistant cases.


INTRODUCTION
Immune checkpoint inhibitors (ICIs) have become a cornerstone in cancer treatment, demonstrating lasting efficacy even in patients with metastatic cancer, and are increasingly employed in (neo)adjuvant and maintenance therapy. [1]However, this has also resulted in the emergence of immune-related adverse events (irAEs), which are strongly associated with but not limited to immune activation associated with antitumor immune responses. [2]Long-term implications and management for irAEs are essential in improving survival with ICIs.
The liver is one of the frequently involved organs in irAE, along with the skin, gut, endocrine gland, and lungs. [3]Incidence of ICI hepatitis is around 5%-10% of patients treated with ipilimumab, nivolumab, pembrolizumab as single agents but increases as high as 25%-30% in ipilimumab and nivolumab combination therapy. [4]Steroids are advised as the initial course of treatment, but there are limitations to the current recommendations as the guidelines are derived largely from expert opinion and case studies. [5]n this study, we aim to conduct a comprehensive review of the treatment approaches and responses for ICI hepatitis, primarily to steroids and secondary immunosuppressants as needed.We further explore the response with rechallenge with an ICI and the recurrent rate of ICI hepatitis.

Literature search and eligibility
This study was prospectively registered at PROSPERO (registration number: CRD42023450088) and followed the MOOSE reporting guidelines (Supplemental Table S1, http://links.lww.com/HC9/B40).We searched PubMed/MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials (CENTRAL) databases in July 2023 based on keywords including currently approved "immune checkpoint inhibitors" (anti-Programmed cell death protein 1 (PD-1)/Programmed Death-Ligand 1 (PD-L1), anti-CTLA-4, and anti-LAG3) and "hepatitis" (complete search strategy provided in Supplemental Table S2, http://links.lww.com/HC9/B40) as keywords by investigator (Soo Young Hwang).Two independent researchers (Soo Young Hwang and Pinghsin Hsieh) reviewed the eligibility of the studies independently, and any disagreement was resolved upon discussion between the 2 researchers.Studies that have a description of steroid usage as a treatment for ICI hepatitis or any other treatment for ICI hepatitis were included.Non-English studies, case reports, meeting abstracts, studies on data that were reported in included studies, and studies with insufficient data were excluded.

Data extraction
From the eligible studies, we extracted the name of the first author, publication year, country, study design, number of patients with ICI hepatitis, stage of ICI hepatitis, cancer type and stage, ICIs, steroid dosage and duration of treatment, secondary immunosuppressive agents, number of patients who were rechallenged, peak ALT levels, adverse events of steroids, and other irAE.The Newcastle-Ottawa Scale (NOS) was applied to assess the risk of bias in the observational studies.

Statistical analysis
Meta-analysis of proportions was performed based on the number of patients treated with steroids and the number of patients requiring a secondary immunosuppressant as the primary outcome.Secondary outcomes were the proportion of patients with ICI hepatitis who were rechallenged with an ICI and the proportion of ICI hepatitis recurrence.The proportion of each study outcome was calculated using a logit transformation.The random effects model was used to obtain the summary estimates, and the summary results were displayed in forest plots.The Q and Higgins I2 statistics were calculated to evaluate the heterogeneity in the included studies. [7]Publication bias was visually assessed by plotting effect size against sample size (ie, funnel plot) (Supplemental Figure S1, http://links.lww.com/HC9/B40).We performed additional analyses to further explore the heterogeneity of the study.These included subgroup analysis on the country of origin and tumor type, with a focus on melanoma (Supplemental Figure S4, http://links.lww.com/HC9/B40).
A meta-regression analysis was performed based on the primary outcome with moderators, including the percentage of patients who received combination treatment and the percentage of patients with advanced hepatitis (grade 3-4).In addition, we conducted a metaregression analysis based on the primary outcome and the year of publication.In addition, the association between the number of patients with ICI hepatitis who did not receive any intervention and the percentage of grade 1-2 hepatitis was investigated through a metaregression analysis.

RESULTS
Through a comprehensive search of the 3 databases, 4358 potentially eligible studies were identified and independently screened with an in-depth full-text screening of 130 studies and 44 studies included for final analysis  (Figure 1; Tables 1-3).

Baseline characteristics
A total of 1856 patients with ICI hepatitis were included.Five hundred ninety (31.7%) of the patients developed grade 1-2 hepatitis, and 1,043 (56.0%) of the patients developed grade 3-4 hepatitis.

Steroid as a first-line treatment of ICI hepatitis
One thousand one hundred eighty-four patients out of a total of 1864 patients received corticosteroid treatment Table 2.The duration of treatment varied considerably across the studies, ranging from 3 to 361 days.Similarly, there was substantial variation in dosage, from oral prednisone at 0.5 mg/kg to i.v.methylprednisolone at 2 mg/kg.In total, 32 studies reported on steroid-refractory cases that necessitated the use of second-line immunosuppressants.Mycophenolate mofetil was the predominant agent used in 68 out of 82 cases (82.9%).Other treatments included infliximab in 5 out of 82 cases (6.1%), azathioprine in 3 out of 82 cases (3.7%), and 1 case each for rituximab, gamma globulin, tacrolimus, and cyclosporine.A summary estimate of the proportion of steroid-refractory hepatitis in a random effects model was 16% (95% CI: 11%-23%) (Figure 2).There was moderate heterogeneity (I 2 = 60%) in the analysis.The funnel plot (Supplemental Figure S1, http://links.lww.com/HC9/B40) showed no visual asymmetry, and statistical analysis showed no evidence of publication bias (p < 0.001).Subgroup analyses based on the country of origin did not demonstrate statistically significant differences in the proportion of patients requiring additional immunosuppressants (chi-square 5.71, df = 3, p = 0.13) (Supplemental Figure S3, http://links.lww.com/HC9/B40) and there was no statistically significant association with the publication year (coefficient = −0.031,p = 0.784) (Supplemental Figure S5, http://links.lww.com/HC9/B40).The proportion of patients requiring additional immunosuppressants was not statistically associated with percentage of combination ICI therapy (coefficient = −0.461,p = 0.546) or percentage of grade 3-4 hepatitis (coefficient = 0.03, p = 0.976).

DISCUSSION
Steroid treatment was the primary intervention in over 75% of patients with ICI hepatitis while 16% of the patients who received steroids required a secondary immunosuppressant in management.An estimated 23% of patients, mostly with grades 1-2 hepatitis, did not require any intervention.Of those who were rechallenged with an ICI, only 22% of the patients experienced a recurrence of ICI hepatitis.Steroids are the treatment of choice given that it is considered that high-dose glucocorticoids do not interfere with the antitumor response of ICIs but there are also controversial studies against this. [1,53]urrent AGA guidelines suggest liver monitoring for grade 1 hepatitis, ICI discontinuation for grade 2 and higher, and if the patient is symptomatic of liver toxicity, an equivalent of prednisone 0.5-1.0mg/kg/d should be administered for grade 2 hepatitis.For grade 3 hepatitis, initiation of an equivalent of 1-2 mg/kg of methylprednisone is recommended, and a second-line immunomodulator such as an azathioprine or mycophenolate mofetil can be considered if there is no clinical improvement in 3-5 days.For grade 4 hepatitis, permanent discontinuation of ICI and initiation of an equivalent of 2 mg/kg/d of methylprednisone is recommended. [5]Third-line immunosuppressive therapy brought into consideration is anti-thymocyte globulin for ipilimumab-induced hepatitis or tacrolimus, whereas infliximab is not recommended. [4]everal studies included in our analysis asserted that there is greater risk than benefit in the use of high-dose steroids compared to low-dose steroids and association with poor survival. [9,16,22,27,49]This can be interpreted by 3 hypotheses: (1) patients who are treated with high-dose steroids have more advanced hepatitis; (2)

STEROID-REFRACTORY ICI HEPATITIS AND ICI RECHALLENGE
| 11 patients with advanced cancer treated with ICIs are at higher risk for side effects of immunosuppression, especially infection; and (3) high-dose steroids compromise the effectiveness of ICIs.Li et al [16] compared 87 patients in the ≥ 1.5 mg/kg methylprednisone equivalent group and 128 patients in the < 1.5 mg/kg group with grade 3-4 ICI hepatitis and reported that there was no difference in the development of steroid-refractory hepatitis but longer exposure and higher incidence of infection.However, the high-dose steroid group also had a higher percentage of ipilimumab and nivolumab combination therapy, which can contribute to a higher risk of disease. [16]Corticosteroids can inhibit the antitumor immune response of ICIs by suppressing low-affinity memory T cells, particularly in a higher dose and earlier administration timing. [54]nti-CTLA-4 mAbs have been associated with a higher incidence of ICI hepatitis compared to anti-PD1/ anti-PD-L1 mAbs, and combination therapy was considered a higher risk than monotherapy, although our study did not demonstrate a statistically significant relationship. [10,17,47]Several studies have suggested that specific histopathologic patterns may correlate with the type of ICI used.Furthermore, these studies indicate that treatment responses may vary based on the characteristic histopathologic pattern of ICI hepatitis.De Martin et al [33] observed a more prevalent pattern of granulomatous hepatitis with anti-CTLA-4 mAbs and a more heterogeneous pattern, mainly lobular hepatitis in anti-PD-1/PD-L1 mAbs.Different histopathologic patterns were also associated with different treatment responses.A study of 20 biopsied patients reported that patients with an acute granulomatous profile defined by the presence of granulomas or acute hepatitis with a toxic profile defined by the presence of eosinophilic polynuclear cells had a better response to corticosteroids, whereas patients with a cholangitic lesion with recorded bile duct lesions had a worse response. [50]s a second-line immunomodulator, mycophenolate mofetil was used in the majority of cases refractory to steroids.Interestingly, infliximab, which was not recommended in the AGA guidelines due to potential idiosyncratic liver injury, was the second-line drug of

Random effects model
Heterogeneity: I 2 = 60%, τ 2 = 0.8836, p < 0.01 Leroy et  choice in 5 cases and azathioprine in 3 cases. [5][57] Azathioprine, traditionally the first-line steroid-sparing agent for autoimmune hepatitis, is less favored in ICI treatment.This is due to its slow onset of immunosuppressive effect, which can take several months to reach peak efficacy.In addition, azathioprine's metabolites can potentially cause hepatotoxicity, further complicating its use in patients already experiencing liver inflammation. [31,58]While the selection of secondline immunomodulators originates from agents used to manage autoimmune hepatitis, it is worth noting that ICI hepatitis exhibits distinct characteristics compared to autoimmune hepatitis, including analytic factors such as lower levels of gammaglobulins, immunoglobulin G, and ANAs. [37]iagnosis and management of ICI hepatitis are challenging in that it is a distinct etiology that is a DILI but also has components of immunological characteristics.ICI hepatitis is a clinical diagnosis of exclusion, and certain adjunctive parameters, such as the RUCAM score, were used to assist in determining whether hepatitis is a DILI. [59]Also, as the majority of studies for ICI hepatitis are conducted on patients with advanced cancer, such as patients with stage 4 melanoma or nonsmall cell lung cancer, hepatic metastases can be a confounding factor in the evaluation of ICI hepatitis. [10,25]CIs were rechallenged after resolution or improvement to grade 1 hepatitis in an estimated 40% of the cases.Recurrence of ICI hepatitis was present in 22% of all rechallenged cases, mainly in anti-PD-1/PD-L1 agents, and was noted to be not as severe as the initial event. [34,45,48]Hountondji et al [48] suggested that rechallenge was even possible after grade 3-4 hepatitis.ICI rechallenge is important because patients at advanced cancer stage have limited options for treatment and because irAEs, including ICI hepatitis, have been associated with improved antitumor efficacy and overall survival. [44,46,47,60]Our findings suggest that rechallenge of ICIs should be reconsidered more frequently after successful treatment of ICI hepatitis.Two studies compared the outcome between patients who underwent ICI rechallenge and those who did not; Simonaggio et al [34] found no significant difference in median progression-free survival time between the rechallenged and non-rechallenged groups, including irAE from other systems.Similarly, Miah et al [47] reported no difference in best overall response or time to death between these groups.However, these findings need to be interpreted cautiously due to the potential for substantial selection bias based on the severity and treatment response of ICI hepatitis.It is also critical that rechallenge would often involve a different regimen, such as switching the class from anti-CTLA4 to anti-PD (L)1 therapy or de-escalation from combination therapy to monotherapy. [11,14,21,37,38,48,51]ur study is the first meta-analysis to quantify the prognosis and treatment response of ICI hepatitis with steroid treatment as the primary treatment.However, our study also had several limitations.First, the variability in the dosage and duration of steroids were high between studies, and it could have been an overgeneralization in estimating the effect of steroids on whether patients received steroid treatment or not.Second, not all studies reported patient characteristics we considered important.For example, while earlier studies provided the detailed dosage and regimen of ICI therapy, most recent studies only included broad categories of ICI therapy used, potentially introducing greater heterogeneity into the analysis.Lastly, although we determined that this is minimal in our study, there is still a possibility of publication bias.